PowerPointPrsentation

1
The InGenious HyperCare European Network A3.
JRP on Genetics and Genomics of Sodium
Homeostasis in the Pathogenesis of Hypertension
and Left Ventricular Hypertrophy
ENDOGENOUS OUABAIN (EO) from
genotypes to cardiovascular structure and function
Tatiana Kuznetsova University of Leuven, Belgium
2
Outline

• Endogenous ouabain possible mechanism.
• Preliminary results
• Perspectives

3
Endogenous ouabain

• In genetic forms of HT, salt sensitivity may
  result from various mutations affecting
  cytoskeleton proteins (such as adducin), ion
  transporters, or endocrine/paracrine factors
  (such as endogenous ouabain and aldosterone).
• In experimental studies, EO had direct effects on
  BP and was associated with TOD (Ferrandi M. et
  al, Front Biosci 2005).

4
.
Structural formula of ouabain

• Ouabain
• cardiotonic steroid (analogue of digitalis)
• cardenolides

5
Modulator of the Na- K pump
EO through direct Na-K pump interaction
Heart, vessels
Kidney
a1 Na-K pump Src-EGFr-dependent Tyr
phosphorylation
Classical a2 Na-K pump inhibition
Overall tubular Na reabsorption
Na/Ca exchange
Ca2i
Volume expansion
Hypertrophy Hypertension
Ferrari P et al., Am J Physiology
2006290R529-R535
6
Infusion in rats (15 mg/kg/day)
Plus oral treatment with PST 2238 (10 mg/kg ) or
amlodipine (5 mg/kg)
Systolic BP

mmHg


Left ventricle weight
1.85
1.75
LVW / tibia lenght


1.65
1.55
1.45
control
OS
OS PST 2238
OS amlodipine
plt0.05, plt0.01 vs control plt0.05, plt0.001
vs ouabain
7
Objective

• We investigated the distribution of plasma
  ouabain in the general population in relation to
  LV structure and function, arterial phenotypes,
  and BP.
• We explored the association of LV and arterial
  phenotypes with genes involved in the
  biosynthesis of EO.

8
Epidemiological methods

• Randomly recruited families (Flemish Study on
  Environment, Genes and Health Outcomes)
• Standardised and validated questionnaires
• A single observer did the echocardiographical
  examinations by means of Vivid 7 ultrasound
  scanner (GE Vingmed, Horten, Norway)
• We measured plasma EO in 434 subjects by
  radioimmunoassay, using a specific antiserum.

9
LV phenotypes
EF ()
Teichholz Volume
IVST - PWT
RWT
LVDD
10
Transmitral blood flow vs pulsed Tissue Doppler
Imaging
A
E
Aa
Ea
11
Clinical characteristics
P?0.05
12
Echocardiographic characteristics
P?0.001
13
Association with LV wall thickness
LV wall thickness
RWT
Posterior wall
Septum
Ouabain quartiles (pmol/L)
Adjusted for gender, age, bmi, sbp, and
antihypertensive treatment
14
Association with LV mass and carotid IMT
LVM
IMT
Ouabain quartiles (pmol/L)
Adjusted for gender, age, bmi, sbp, and
antihypertensive treatment
15
Association with BP
SBP
DBP
All n434
Untreated n324
Ouabain quartiles (pmol/l)
Adjusted for gender, age, age2, bmi, and
antihypertensive treatment
16
Familial aggregation of EO level

• Intrafamilial correlation coefficient for EO was
  0.15 P 0.023
• Candidate genes were selected from a putative
  steroid biosynthetic pathway (Murrell J.R. et al,
  Circulation 2005)

17
Steroidogenic genes

• Three genes of the biosynthetic pathway of EO are
  over-expressed in MHS genetic
  hypertensive rats
• Cholesterol side chain cleavage cytochrome P450
  CYP11A1
• 3ß hydroxy-steroid deydrogenase HSD3B1
• Lanosterol synthase LSS.
• In hypertensive patients, plasma EO was
  associated with variation in HSD3B1 and
  LSS.

18
LV phenotypes by the HSD3B1 and CYP11A1 genes
11
12 22 P
HSD3B1 (rs2236780 and rs3765945) GG
haplotype N
--- 70 438
TDI Ea/Aa ---
1.02 1.18 0.0026 CYP11A1
(rs11638442) N
182 233 93
LVM (g) 174.5
176.7 160.9 0.0037
19
Perspectives

• Our preliminary results show that BP and LV wall
  thickness are associated with plasma EO.
• Genetic variation in the EO pathways, via BP
  and/or LV structure/function might contribute to
  risk stratification in clinical practice, pending
  a full screen of the candidate genes.
• Phenotype-genotype associations involving
  functionally relevant SNPs will then be
  replicated in ongoing echocardiographic studies
  within the consortium (Kraków, Gdansk,
  Novosibirsk, Padova, and Valencia).